Human Reproduction, Vol.27, No.1 pp. 153–158, 2012
Advanced Access publication on October 24, 2011 doi:10.1093/humrep/der341
ORIGINAL ARTICLE Infertility
The reliability of the histological
diagnosis of endometritis in
asymptomatic IVF cases: a multicenter
observer study
J.C. Kasius 1,*, F.J.M. Broekmans 1, D.M.D.S. Sie-Go 2, C. Bourgain 3,
M.J.C. Eijkemans 4, B.C. Fauser 1, P. Devroey 5, and H.M. Fatemi 5
1
Department of Reproductive Medicine and Gynaecology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands 3Department of Pathology, Academic
Hospital at the Dutch-speaking Brussels Free University, 1090 Brussels, Belgium 4Julius Center for Health Sciences and Primary Care,
University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands 5Center for Reproductive Medicine, Academic Hospital at the
Dutch-speaking Brussels Free University, Brussels 1090, Belgium
2
*Correspondence address. Fax: +31-88-7555433; E-mail: [email protected]
Submitted on February 13, 2011; resubmitted on July 12, 2011; accepted on August 17, 2011
background: Chronic endometritis is associated with abnormal uterine bleeding, recurrent abortion and infertility. It is a subtle
condition, and therefore is difficult to diagnose. The diagnosis is ultimately based on the presence of plasma cells in the endometrial
stroma on histopathological examination. Literature on the reproducibility of the diagnosis of chronic endometritis is lacking. Therefore,
the aim of the current study was to assess the interobserver agreement of two pathologists in diagnosing chronic endometritis in asymptomatic, infertile patients.
methods: In the context of a randomized controlled trial, an endometrial biopsy was taken during a screening hysteroscopy prior to IVF.
All endometrial samples were independently examined by two pathologist. The slides diagnosed with chronic endometritis were replenished
with a random sample of the remaining slides up to a total of 100, then exchanged between the two pathologists and reassessed.
results: Of the 678 patients who underwent hysteroscopy, 19 patients were diagnosed with at least possible chronic endometritis
(2.8%). Perfect agreement between the pathologists, before and after inclusion of 13 slides with additional immunohistochemistry staining,
was found in 88 and 86% of reviews, respectively. The interobserver agreement was substantial, with kappa-values of 0.55 and 0.66,
respectively.
conclusions: The interobserver agreement in diagnosing chronic endometritis in asymptomatic infertile patients was found to be
substantial. Although the diagnostic reliability is sufficient with the methods in the present study, the low prevalence and unknown clinical
significance of endometritis warrants further study.
Key words: chronic endometritis / endometrial pathology / infertility / IVF / plasma cell
Introduction
Chronic endometritis is a persistent inflammation of the inner lining of
the uterine cavity. It is thought to be associated with abnormal uterine
bleeding, recurrent abortion and infertility (Greenwood and Moran,
1981; Polisseni et al., 2003; Romero et al., 2004). In 12–46% of the
hysteroscopy-guided endometrial biopsies in infertile patients,
chronic endometritis was found to be present (Féghali et al., 2003;
Polisseni et al. 2003; Cicinelli et al., 2005; Johnston-MacAnanny
et al., 2010). Detection and treatment has been reported to significantly improve pregnancy rates (Féghali et al., 2003).
However, diagnosing chronic endometritis is known to be rather
difficult. It is usually asymptomatic and hard to identify by most diagnostic tests. Although hysteroscopy enables direct visualization of
the endometrial lining, variable results have been reported on its diagnostic accuracy in the detection of chronic endometritis (Polisseni
et al., 2003; Cicinelli et al., 2005). Histological examination of an endometrial biopsy is known as the golden standard. Abnormal percentages of lymphocytes, leukocytic infiltration of both glands and
stroma, and the presence of eosinophils or macrophages are the
histological features described to be associated with chronic
inflammation (Greenwood and Moran, 1981; Dechaud et al., 1998;
& The Author 2011. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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154
Matteo et al., 2009; Adegboyega et al., 2010). Nevertheless, the presence of plasma cells in the endometrial stroma is the only histological
criterion that is generally accepted for the diagnosis of chronic endometritis. The search for plasma cells can be interfered with or hampered by many conditions, such as mononuclear inflammatory cell
infiltrates, stromal cell proliferation, the plasmacytoid appearance of
stromal cells or a pronounced predecidual reaction in a late secretory
endometrium (Greenwood and Moran, 1981; Crum et al., 1983;
Adegboyega et al., 2010). As the presence of only one plasma cell is
sufficient to diagnose chronic endometritis, histological detection
obviously is time-consuming and difficult. Despite the fact that immunohistochemical markers that specifically stain plasma cells simplify the
diagnostic decision, additional staining is not routinely provided in daily
practice (Crum et al., 1983; Bayer-Garner et al., 2004).
The endometrial biopsy and histological examination has been
widely used as a part of the infertility work-up in order to assess endometrium development during the luteal and/or the follicular phase.
The accuracy as well as intra- and interobserver agreement of an
endometrial biopsy for diagnosing luteal phase defects has been
assessed thoroughly (Scott et al., 1993; Smith et al., 1995; Duggan
et al., 2001; Myers et al., 2004). However in the literature, there is
a lack of studies accessing the intra- or interobserver variation in diagnosing chronic endometritis. Therefore, the aim of this study was to
assess the interobserver agreement in diagnosing chronic endometritis
in asymptomatic, infertile patients.
Materials and Methods
Patients
In the period from June 2007 until September 2008, endometrial biopsies
were obtained in the context of the TEA-trial (‘Treatment Efficacy
of unsuspected uterine Abnormalities’) (Fatemi et al., 2010). The aim of
this randomized controlled trial was to assess the treatment efficacy
of intrauterine abnormalities on subsequent IVF or ICSI treatment (trial
register number: NCT00830401). Patients under the age of 43 years indicated for fertility treatment at the University Medical Center Utrecht
(UMC-U) or the Academic Hospital at the Dutch-speaking Brussels Free
University (UZ-VUB) underwent office hysteroscopy prior to a first
IVF/ICSI treatment cycle. Exclusion criteria were symptoms suggestive
of intrauterine pathology, abnormalities at transvaginal ultrasound or a
prior hysteroscopy examination. The Institutional Review Board of the
two participating centers approved of the study, and informed consent
was obtained.
Hysteroscopy and endometrial biopsies
The hysteroscopy procedures were scheduled in the follicular phase of the
menstrual cycle (Day 3 – 15), 1 – 3 months before starting the IVF/ICSI
treatment. All procedures were performed in an outpatient setting,
making use of a 5-mm outer-diameter continuous flow Bettocchi hysteroscope with 308 direction of view (Karl Storz Endoscopy, Stöpler Medical
Instruments, Utrecht, The Netherlands and Olympus Belgium N.V., Aartselaar, Belgium). At the end of each procedure, an endometrial biopsy was
obtained. At the UMC-U, a grasping forceps (Karl Storz, Endoscopie
Nederland B.V., Nieuwegein, The Netherlands) was used to perform
the biopsy from the posterior wall, halfway along the distance between
the inner cervical os and the uterine fundus. At the UZ-VUB, a Pipelle
de Cornier under local anesthesia was used to perform a blind biopsy
(Laboratoire CCD, Paris, France).
Kasius et al.
Histological examination
The endometrial biopsies were placed in a fixative of 4% phosphatebuffered formaldehyde and processed routinely into one or two hematoxylin and eosin (HE) stained slides per patient. At each research hospital,
one pathologist, with a special interest and expertise in gynecological pathology, examined all endometrial samples obtained at that research hospital, independently from the other pathologist. Both pathologists were
aware of the study design. However, the only clinical information provided
was the day of the menstrual cycle on which the biopsy was taken and
whether oral contraceptives had been used. A standard form was used
to record the results of classifying the endometrial tissue samples, the
presence or absence of plasma cells and other inflammatory cells (i.e. lymphocytes, neutrophilic granulocytes, histiocytes/macrophages and eosinophilic granulocytes) (Mazur and Kurman, 2005). An abnormal prevalence
of different inflammatory cells, or lymphocytes destructing the endometrial
tubuli were suggestive of chronic endometritis. However, the presence of
plasma cells ultimately set the diagnosis of chronic endometritis. According
to the findings during histopathology examination, the concluding diagnosis
was reported by the pathologist. The diagnostic categories were as
follows: no chronic endometritis, possibly chronic endometritis and
evident chronic endometritis.
In cases where the diagnosis remained doubtful after the assessment of
the HE-stained tissue sections, additional immunohistochemistry for the
plasma cell marker CD138, alone or in combination with staining for
the B-cell markers CD20 or CD79a, was performed. For CD138, the
Clone B-B4 antibody (batch 605, Serotec) was used by applying a dilution
of 1:1000. For plasma cells and B-lymphocytes CD79a, the Clone JCB117
antibody (batch 2791, DAKO) was used at a dilution of 1:200. For
B-lymphocytes CD20, the Clone L26 antibody (batch 083, DAKO) was
used at a dilution 1:400. For all antibodies, antigen retrieval in citrate
buffer was applied and staining was done with the Bond-Max autostainer
(Leica).
Histological revision for observer agreement
The slides of patients diagnosed with possible or evident chronic endometritis, according to the first histological examination, were replenished by a
sample of slides from the patients who were not diagnosed with chronic
endometritis, up to a total of 50 per research center. The added patients
without chronic endometritis were matched to the patients with chronic
endometritis for the research hospital and the day of the menstrual
cycle on which the hysteroscopy was performed and the biopsy was
taken. The 50 slides of the replenished sample per research center
were exchanged between both pathologists for a second evaluation.
The histological revision was performed similarly to the original examination. Initially, only the HE stained slides were assessed. Thereafter, the
pathologist could alter his or her opinion if additional immunohistochemistry appeared to be present.
Statistical analysis
The pathologists’ findings were statistically analyzed, using SPSS version 15.1
(SPSS Inc., Chicago, IL, USA) and R2.9.2 (R Development Core Team,
2009). The agreement between both pathologists on the slides of the histological reassessed sample was calculated. Their agreement on the diagnostic
categories was evaluated for the findings based on HE stained slides alone or
in combination with additional immunohistochemical staining. The interobserver agreement was calculated as the percentage of perfect agreement and
corresponding weighted kappa-value. Kappa is a measure for agreement
between observers corrected for the agreement expected to occur by
chance (k ¼ (Observed agreement 2 Agreement by Chance)/(1 2
Agreement by chance)). A kappa-value of ,0.20 is interpreted as slight
155
Reproducibility of the diagnosis of endometritis
agreement, a value between 0.21 and 0.40 as fair agreement, a value
between 0.41 and 0.60 as moderate agreement, a value between 0.61 and
0.80 as substantial agreement and a value of 0.81 – 1.00 as almost perfect
agreement (Landis and Koch, 1977). The weighted kappa takes into
account the ordinary scale of categorical variables, so that different levels
of agreement between categories contribute to the kappa-value (Fleiss
and Cohen, 1973).
Results
A total of 678 asymptomatic, infertile patients were included in the
TEA trial and underwent office hysteroscopy (Fig. 1). The observed
hysteroscopy findings are reported in Table I. The endometrial
tissue samples of 606 patients could be adequately examined by the
two pathologists (Table II). Histological examination failed in 11% of
the participants, due to inability to complete the hysteroscopy
procedure (1%), to perform the endometrial biopsy (3%) or to
obtain sufficient endometrial tissue (7%).
Out of the population of 606 successfully biopsied patients, at
first examination 587 were diagnosed as ‘no chronic endometritis’
(86.5%), 2 were diagnosed with ‘possible nonspecific chronic
endometritis’’ (0.3%) and 17 patients with ‘evident nonspecific
chronic endometritis’’ (2.8%).
The slides of the 19 patients in whom possible or evident chronic
endometritis was detected, added up with a matched selection out
of the other slides up to a total of 50 per research hospital, were
revised by the pathologist from the other research center. In this histological reassessed sample of 100 slides, the slides of 13 patients
were additionally stained with immunochemical markers. Between
the patients contributing to the analyzed histological revision sample
(n ¼ 100) and those who did not (n ¼ 506), no significant differences
were found regarding day of the cycle on which the hysteroscopy was
performed, age, body mass index, duration of child wish, cause for the
infertility or the rate of presence of an intrauterine abnormality at
hysteroscopy.
Table I Findings at hysteroscopy examination.
Findings
Prevalence
%
........................................................................................
Normal cavity
94
Abnormal cavity
13
12.1
12
11.2
Myoma
1
0.9
Adhesion
0
0.0
Septum
2
1.9
Polyp
Total
87.9
107
100
Table II Patient characteristics of the sample of IVF/
ICSI patients used for the histological revision.
Variables
n 5 100
........................................................................................
Age
Duration of subfertility (years)a
32.98 + 3.96
3.05 + 2.24
Body mass index
24.41 + 5.20
TMCb
65.67 + 120.32
Day of menstrual cyclec
9.66 + 3.74
Infertility woman
1. Primary
63 (63%)
2. Secondary
37 (37%)
Cause infertility
Figure 1 Flowchart illustrating the enriched sample method.
Shown is the number of patients at each step towards the group of
cases in which the endometrial samples were histologically examined
by both pathologists and analyzed for the interobserver agreement.
Cases initially diagnosed with chronic endometritis were replenished
by a sample of randomly selected patients not initially diagnosed with
chronic endometritis. Matching was performed for research center
and day of menstrual cycle on which the endometrial biopsy was
obtained. 1The trial ‘Treatment Efficacy of unsuspected uterine
Abnormalities’ on subsequent IVF or ICSI treatment (register
number: NCT00830401).
1. Idiopathic
43 (43%)
2. Andrologic factorb
47 (47%)
3. Subfertile femaled
10 (10%)
Values are expressed as mean + Standard deviation.
a
Duration of attempt to become pregnant, in cases of secondary infertility calculated
from the last ongoing pregnancy.
b
Defined as TMC (total motile count, semen volume (ml) * concentration
spermatozoa (*109/ml) * Grade A and B spermatozoa motility (%)) , 20 × 106.
c
Day of the menstrual cycle on which the endometrial biopsy was obtained.
d
Due to tubal pathology (incl. endometriosis Grade III and IV), anovulation or cervix
factor.
156
Kasius et al.
Observer agreement in diagnosing chronic
endometritis
The interobserver agreement was assessed in the sample of the slides
of 100 patients, which were assessed by both pathologists. Based on
solely the HE-stained tissue specimens, the pathologist at the UMC-U
detected evident chronic endometritis in 12 patients (Table III), and in
1 case, the diagnosis remained doubtful. The pathologist at the
UZ-VUB identified evident and possible chronic endometritis in 14
and 3 patients, respectively. They reported similar diagnostic categories in 88% of all 100 patients. The kappa-value for interobserver
agreement was 0.546 (95% CI: 0.351–0.741), which represents
moderate agreement.
Agreement analysis was also performed, after replacing the 13 HE
stained slides by the corresponding slides with an additional immunohistochemistry staining. The pathologist at the UMC-U diagnosed
evident and possible chronic endometritis in 14 and 5 patients
(Table III). The findings of the pathologist at the UZ-VUB were 15
and 4, respectively. Perfect agreement on the diagnostic category
appeared in 86%. The kappa for interobserver agreement when
additional staining using immunohistochemical markers was included
was 0.659 (95% CI: 0.463–0.855), which is interpreted as substantial
agreement.
Discussion
Chronic endometritis generally is an asymptomatic condition and
therefore difficult to diagnose. Although some subtle endometrial
alterations have been described to be indicative for chronic endometritis, the diagnosis ultimately relies on the presence of plasma cells at
histological examination (Greenwood and Moran, 1981; Dechaud
et al., 1998; Matteo et al., 2009; Adegboyega et al., 2010). The
current study demonstrates that the interobserver agreement in diagnosing nonspecific chronic endometritis in asymptomatic patients prior
to a first IVF/ICSI treatment is substantial.
It is rather surprising that the interobserver agreement reached the
level of ‘substantial’, while unequivocal and easy to determine criteria
for the diagnosis nonspecific chronic endometritis are currently
absent. The diagnostic criterion for the identification of plasma cells
with or without additional specific staining, as applied in the present
study, may come with difficulties. Plasma cells generally are present
in small amounts and may be mimicked or blurred by certain conditions of the endometrium or endometrial and inflammatory cells
(Greenwood and Moran, 1981; Crum et al., 1983; Adegboyega
et al., 2010). In the present study, endometrial tissue was obtained
by a hysteroscopy-guided biopsy, which resulted in only a small
sample of endometrium available for histological examination. In the
UMC-U, a grasping forceps was used instead of a Pipelle de
Cornier, which resulted in even smaller amounts of material in
some cases. Moreover, the slides of the research hospitals also had
a slightly different appearance due to variation in the routine processing of the endometrial tissue in the laboratories (difference in color
and amount of tissue on one slide). Another limitation in the search
for plasma cells may have been the absence of a standard additional
immunohistochemistry staining on all endometrial biopsies.
However, in daily practise, immunochemical markers are not routinely
provided either. Taking into account all factors that could have hampered the diagnosis of chronic endometritis, the substantial reproducibility between observers is rather satisfying.
The results of the present study were based on a sample of
100 patients out of the whole study population in which a
hysteroscopy-guided endometrial biopsy was obtained. The cases
were selected on a specific criterion, namely the diagnosis of at
least possible chronic endometritis by a pathologist, whereas the controls were randomly selected. This may have influenced the statistic
assumption underlying the calculation of the kappa-values, though it
seems not plausible to have occurred in this situation. Another consequence has been the difference in the prevalence of chronic endometritis between the sample and the whole study population. Thus, the
use of an enriched sample instead of the whole patient population may
have affected the study results. In our setting, it was the only feasible
study design. Still, most processes of diagnosing based on operator
judgment include elements of information on the likelihood of
finding an abnormality and the specific question that has been put
forward by, for instance, the clinician. As the pathologists were
aware of these aspects, the approach chosen may not be really
Table III Histological diagnosis by the pathologist of the UZ-VUB (horizontal) and the pathologist of the UMC-U
(vertical) of the analyzed, revised group of 100 patients.
UZ-VUB
HE
UMC-U
...............................................
a
No
a
Possibly
UZ-VUB
CD
a
UMC-U
....................................................
Noa
Evident
Possiblya
Evidenta
.............................................................................................................................................................................................
Noa
79
0
4
Noa
76
1
4
Possibly
2
1
0
Possiblya
2
1
1
Evidenta
6
0
8
Evidenta
3
3
9
a
Agreement
88%
Agreement
86%
Weighted k
0.546
Weighted k
0.659
95% CI
(0.351–0.741)
95% CI
(0.463–0.855)
Also, the level of perfect interobserver agreement and corresponding kappa-values of diagnosing possible or evident chronic endometritis.
Results split up for the findings based on the HE stained slides (on the left) and the findings if also the slides additionally stained with immunohistochemical markers (CD) are included
(on the right).
a
Referring to no chronic endometritis, possibly chronic endometritis and evident chronic endometritis.
157
Reproducibility of the diagnosis of endometritis
remote from daily practice and thereby serves well as a model for
reliability assessment.
Among the various endometrial abnormalities that can be enlightened by endometrial biopsy, the interobserver variation on hyperplasia and the luteal phase defect have been widely assessed. The WHO
classification of endometrial hyperplasia of 1994 differentiates
between simple and complex hyperplasia with or without atypia.
The first study evaluating the agreement between six gynecologists
on this WHO classification found a maximum kappa-value of 0.25
(95% CI 0.23 –0.28) (Skov et al., 1997). Two following studies,
which used slightly different diagnostic categories, found moderate
to substantial agreement between five pathologists, with kappa-values
of 0.47 –0.70 (Kendall et al., 1998; Bergeron et al., 1999).
In diagnosing luteal phase defects, the observer agreement was
found to be somewhat disappointing. In 78 slides of infertile patients,
the reproducibility of endometrial dating was assessed. The agreement
among four pathologists on the dating categories ‘proliferative’,
‘secretory’, ‘menstrual’ or ‘undateble’ was substantial (maximum
kappa-value: 0.70) (Duggan et al., 2001). Furthermore, the observer
agreement based on the diagnosis of ‘in-phase’ or ‘out-of phase’,
defined as a 2-day difference between the histological date and the
calculated luteal phase date based on the urinary LH surge, was
evaluated. The reproducibility was shown to be moderate, with
kappa-values between 0.4 and 0.6 in biopsies of 82 fertile and 83
infertile patients (Myers et al., 2004).
To the best of our knowledge, reproducibility studies on diagnosing
chronic endometritis are absent. In view of the results of the available
observer studies on endometrial hyperplasia and luteal phase
deficiencies, the reproducibility of diagnosing chronic endometritis is
similar or slightly more promising.
The impact of chronic endometritis on fertility is controversial. The
described prevalence varies widely and trials investigating the reproductive outcome of patients with chronic endometritis have reported
contrary results (Czernobilsky, 1978). The prevalence of chronic
endometritis has been described to be between 0.2 and 46%
amongst infertile women (Wild et al., 1986; Sahmay et al., 1995;
Féghali et al., 2003; Polisseni et al. 2003; Cicinelli et al., 2005; JohnstonMacAnanny et al., 2010). Most recent studies have investigated
a hysteroscopy-guided biopsy and found chronic endometritis in
12 –46%. Those studies concern small patient populations, generally
in which women had clinical symptoms justifying diagnostic hysteroscopy. Since the current study investigated a large group of consecutive women, without specific symptoms suggestive of uterine
pathology, prior to starting a first IVF/ICSI cycle, the relatively low
prevalence was to be expected. Regarding the impact of chronic endometritis on fertility, limited research is published. Recently published
literature has shown that in 33 patients with two or more failed IVF
attempts, the implantation rate of patients with chronic endometritis
was significantly lower than controls without chronic endometritis,
12 versus 33% (Johnston-MacAnanny et al., 2010). However, the
ongoing pregnancy rate did not significantly differ between the patients
of both groups. Moreover, in patients clinically suspected of pelvic
inflammatory disease, the prevalence of infertility did not significantly
differ between patients with or without chronic endometritis
(Haggerty et al., 2003).
The uncertainty on the impact of chronic endometritis on reproductive outcome also determines the importance of its detection.
Future research should be ideally in the form of a sufficiently
powered prospective study in infertile women indicated for assisted
reproductive technology in whom a standard biopsy is taken and
the histopathology is related to subsequent outcome of treatment.
Possibly, the inSIGHT trial, in which hysteroscopy with direct
treatment of visible pathology is performed, with the addition of
standard biopsy will contribute such data (trail register number
NCT01242852). This multicenter trial has recently been started in
The Netherlands. Moreover, a systematic review on individual
patient data may allow for a larger data acquisition that will help assessing the exact significance of endometritis. Once the true impact is
clarified by this future research, the usefulness of an endometrial
biopsy in patients suffering from infertility can be determined. Nevertheless, the present interobserver agreement study has demonstrated
that histological examination of an endometrial biopsy is a reproducible method for the diagnosis of chronic endometritis.
Authors’ roles
Authors J.C.K., F.J.M.B., B.C.F., P.D. and H.M.F. designed the initial
study. F.J.M.B and H.M.F. performed the hysteroscopy procedures.
D.M.D.S.S.-G. and C.B. histologically examined all endometrial
samples. J.C.K. coordinated, collected, analyzed and interpreted the
data. F.J.M.B., D.M.D.S.S.-G., C.B., M.J.C.E. and H.M.F. participated
in analyses and interpretation of the data. J.C.K., F.J.M.B. and H.M.F.
wrote the paper. D.M.D.S.S.-G., C.B., M.J.C.E., B.C.F. and P.D.
revised the manuscript. All authors approved the final draft. J.C.K.
will act as guarantor for the paper.
Conflict of interest
J.C.K., D.M.D.S.S.-G., C.B. and M.J.C.E. declare that they have no conflict of interest. F.J.M.B. is a member of the external advisory board for
Ferring Pharmaceuticals, Hoofddorp, the Netherlands. He receives no
monetary compensation. B.C.F. has received fees and grant support
from the following companies (in alphabetic order): Andromed,
Ardana, Ferring, Genovum, Glycotope, Merck Serono, Organon,
Pantharei Bioscience, Philips, PregLem, Schering, Schering-Plough,
Serono and Wyeth. P.D. has received fees and grant support from
the following companies (in alphabetic order): Anecova, Besins,
Ferring, Merck Serono, and Schering-Plough. H.M.F. is a member of
the external advisory board for MSD/Organon Pharmaceuticals.
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